Title of Invention	PROCESS FOR PREPARING AN ORALLY ADMINISTERED LIQUID PREPARATION
Abstract	Process for preparing an orally administered liquid preparation of a pharmaceutical active substance of the NSAID type in the form of a stabilised suspension, characterised in that (i) the solid active substance is ground in order to produce a particle size spectrum in which at least 90% of the particles are smaller than 50 µm, preferably at least 50% of the particles are smaller than 10 µm, but in particular about 90% of the particles are smaller than 10 µm; (ii) the ground active substance is suspended in a physiologically inert dispersion medium in which the solubility of the active substance is very low; (iii) 0.1 -5 wt.-% of highly dispersed silicon dioxide are added to the dispersion medium with the application of high shear forces; (iv) 0.05 to 2 wt.-% of hydrophilic polymer soluble in the dispersion medium' are added to the dispersion medium; and (v) optionally, one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may, independently of one another, be added to the dispersion medium, the flavourings preferably being added during the final stage of manufacture owing to their foam breaking properties.

Title of Invention

PROCESS FOR PREPARING AN ORALLY ADMINISTERED LIQUID PREPARATION

Abstract

Process for preparing an orally administered liquid preparation of a pharmaceutical active substance of the NSAID type in the form of a stabilised suspension, characterised in that (i) the solid active substance is ground in order to produce a particle size spectrum in which at least 90% of the particles are smaller than 50 µm, preferably at least 50% of the particles are smaller than 10 µm, but in particular about 90% of the particles are smaller than 10 µm; (ii) the ground active substance is suspended in a physiologically inert dispersion medium in which the solubility of the active substance is very low; (iii) 0.1 -5 wt.-% of highly dispersed silicon dioxide are added to the dispersion medium with the application of high shear forces; (iv) 0.05 to 2 wt.-% of hydrophilic polymer soluble in the dispersion medium' are added to the dispersion medium; and (v) optionally, one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may, independently of one another, be added to the dispersion medium, the flavourings preferably being added during the final stage of manufacture owing to their foam breaking properties.

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; rule 13]] "PROCESS FOR PREPARING AN ORALLY ADMINISTERED LIQUID PREPARATION" BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG. (formerly known as BOEHRINGER INGELHEIM PHARMA KG.), a German company, of Binger Strasse 173, D-55216 Ingelheim am Rhein, Germany. The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- - 1 - S018-543J.pri Boehringer Ingelheim Pharma KG Case 5/1232-Ro D-55216 Ingelheim 5 Oral Suspension of Active Substance 10 1. Introduction The present invention relates to orally administered suspensions of pharmaceutically active substances of the NSAID type (nonsteroidal-antiinflammatory drugs), but 15 particularly the antirheumatic agent meloxicam and a process for preparing them. 2. Statement of Problem 20 Various pharmaceutical forms are used for oral administration of drugs. Thus, in addition to solid single-dose forms such as tablets, hard and soft gelatine capsules, liquid forms such as solutions and syrups are also given, in which the dose to be administered can be 25 adjusted by means of the volume given. Solutions and syrups have the advantage that they can be taken easily and safely even by patients who have trouble taking solid, single-dose forms (e.g. children and older 30 patients). However, it should be borne in mind that even with the same dosage and the same method of administration, the activity of the same pharmaceutical substance may vary. 35 These variations mean that the therapeutic effect clinically demonstrated for a drug in a specific - 2 - preparation cannot be achieved with a different preparation of the same drug, and furthermore within a course of treatment one preparation cannot readily be exchanged for another. Preparations which are not 5 therapeutically equivalent are known as "non-bioequivalent". For the oral administration of pharmaceutical preparations, the drug is usually absorbed faster from liquid preparations, particularly solutions, than from tablets or capsules and these drugs are 10 consequently not always bioequivalent (Bauer K. H.; Fromming K.-H.; Fuhrer C, Pharmazeutische Technologie, 5th Edition 1997, Gustav Fischer Verlag, Stuttgart, page 213) . 15 Meloxicam is an antirheumatic agent belonging to the NSAID's. NSAID's are cyclooxygenase inhibitors, whilst meloxicam has been shown to have a selective inhibitory effect on the isoenzyme COX-2 and consequently a reduced risk of undesirable gastrointestinal side effects. For 20 safe administration of meloxicam and other active substances, e.g. other NSAID's, a liquid oral preparation is desirable as an alternative to the solid form (capsule, tablet), particularly in paediatrics. 25 The complex objective of the present invention was primarily to produce an orally administered liquid preparation of meloxicam. The formulation should take effect rapidly when first used in acute cases. However, the substance is preferably used for long-term therapy. 30 In such long-term therapy, the liquid oral formulation should be bioequivalent to other oral formulations (tablet, capsule) in the steady state in order to allow therapy with either a liquid or solid oral formulation as desired. At the same time, the liquid preparation should 35 have a pleasant flavour in order to be acceptable to children and thus ensure that it is taken as specified and - 3 - the treatment is ensured. In addition, the liquid preparation should preferably not contain any ethanol, since the possibility of ethanol having a harmful effect even in physiologically acceptable, non-toxic 5 concentrations cannot be ruled out completely, particularly in children. Moreover, when ethanol is used, there is the risk of abuse by alcohol-dependent patients or relapse on the part of formerly alcohol-dependent patients. The suitability of the formulation for diabetic 10 patients should also be taken into account. To ensure exact dosage of a liquid oral preparation of meloxicam, the preparation should also be homogeneous over a sufficient length of time during its removal from the primary packaging. 15 3. Specification of the Invention One obvious way of preparing a liquid oral formulation of 20 a pharmaceutically active substance is to dissolve the substance in physiologically inert solvents (especially pharmaceutical grade water). However, this approach is unsuitable in many cases. To ensure the desired pleasant taste of a liquid oral formulation, e.g. meloxicam, it is 25 not possible to use solutions, since the substance in the dissolved state has an unpleasant taste of its own. This taste is apparent in all the solvents which can be used for the oral administration of solutions and cannot be adequately masked even by the addition of flavour 30 correcting agents such as flavourings and sweeteners. However, meloxicam does not have a noticeable flavour of its own when the substance is suspended in a physiologically inert dispersion medium for a liquid oral 3 5 preparation and the solubility of meloxicam in the dispersion medium used is very slight. This provided a - 4 - suitable approach to solving the problem. This approach can be applied analogously to other active substances of the NSAID category. Since a clearly noticeable unpleasant taste is present even at a concentration of over 500 µg/ml 5 of dissolved meloxicam, the solubility of this active substance in the dispersion media used must be below this threshold. When a suspension of active substance is used there is the 10 problem that the homogeneity of the suspension has to be ensured for a sufficient length of time during removal from the primary packaging (e.g. glass bottle, 100 ml) to ensure accurate dosing. However, the sedimentation of solids dispersed in liquid media cannot be prevented but 15 only delayed for a greater or lesser period. One conventional approach to delaying sedimentation is, for example, by increasing the viscosity of the dispersing medium by the addition of suitable substances, e.g. organic hydrocolloid forming agents, e.g. cellulose ether, 20 or silicon dioxide as a thickener. Increasing the viscosity of the dispersing agent does, however, have the serious disadvantage that it makes it considerably more difficult to redisperse the sediment formed, to the extent that if the suspension is too viscous it is impossible to 25 reconstitute the suspension at all. Moreover, the caking caused by contact of the individual particles under the effects of gravity during storage of the suspension must be avoided. It is known from the literature to prevent caking by, for example, controlled flocculation of such 3 0 systems by the adsorption of potential-determining ions (Sucker H., Fuchs P., Speiser P., Pharmazeutische Technologie, 5th Edition 1991, Georg Thieme Verlag, Stuttgart, p. 423). The industrial manufacture of stable suspensions by controlled flocculation is subject to 35 limitations, since it is difficult to reproduce the optimum properties of suspension systems of this kind - 5 - owing to the variability of the suspended solid and the stability of the suspension is considerably affected by the adjuvants used. 5 Surprisingly, the suspension of a pharmaceutically active substance of the NSAID type can be stabilised by the addition of small amounts of highly dispersed silicone dioxide in the presence of small amounts of hydrophilic polymers. Because of the low concentration of highly 10 dispersed silicon dioxide and hydrophilic polymer in the dispersion medium, the viscosity is low; unwanted increased in viscosity, which will prevent reconstitution of the suspension, caused by gel-like thickening of the dispersion medium does not occur if at the same time small 15 amounts of hydrophilic polymer which are soluble in the dispersion medium are added to the medium and the silicon dioxide is added to the suspension with the aid of high shear forces. Suitably high shear forces can be produced with a suitable shear-intensive homogenising mixer, e.g. 20 with mixers of the series "Becomix" made by Messrs. A. Berents GmbH & Co. KG, Henleinstr. 19, D-28816 Stuhr, which comprise rapidly rotating homogenisers working on the rotor-stator principle. A circumferential rotor speed of about 25 to 27 m/s is particularly suitable for 25 generating sufficiently high shear forces and is used to introduce the highly dispersed silicon dioxide into the dispersing agent for about 10 - 15 minutes, e.g. using the mixers Becomix RW 60/RW 1000. This produces a special siloid structure which consists of a spongy three- 3 0 dimensional structure of hydratised highly dispersed silicon dioxide shot through with cavities, the active substance being adsorbed onto said structure. Suitable highly dispersed silicon dioxide has a specific 35 surface area of at least 50 m2/g/ preferably 100 to 400 m2/g, for example, whilst a specific surface area of - 6 - about 200 m2/g is particularly preferred (e.g. Aerosil® 200) . The invention relates to a suspension of a 5 pharmaceutically active substance of the NSAID type with suspendable particle size spectrum in a physiologically inert dispersion medium in which the active substance has very little solubility, so that the suspension has no perceptible taste of its own, for oral administration, 10 characterised in that the suspension contains a small amount of highly dispersed silicon dioxide for stabilisation by forming a three-dimensional siloid structure, the three-dimensional siloid structure being produced by adding the silicon dioxide to the dispersion 15 medium under the action of high shear forces, and the suspension additionally contains a small amount of hydrophilic polymer which is soluble in the dispersion medium. 20 The above-mentioned three-dimensional siloid structure consists of crosslinked, swollen and coherent strands of SiO2 between which can be found fairly large cavities filled with dispersion medium. The suspended solid particles of the active substance, e.g. meloxicam, are 25 adsorbed almost exclusively onto the SiO2 strands. In this way, the suspended particles are rapidly and fully wetted and agglomeration of the particles of pharmaceutical substance can be prevented entirely. This results in a suspension of the active substance of 30 exceptional homogeneity and dosing precision. The siloid structure described does not lead to any gel-like thickening of the dispersion medium but rather produces a low viscosity pourable suspension. Figure 1 illustrates the siloid structure described. - 7 - At the same time, the three-dimensional siloid structure acts as a sedimentation stabiliser. The structure described is very bulky and is compressed only slightly and very slowly even by sedimentation. Thus, even after 5 months of storage, the volume of the siloid structure decreases by only about 20%. The reduction in volume caused by sedimentation does not result in undesirable caking; the sediment can be easily and quickly redispersed by the use of extremely slight mechanical forces (e.g. 10 very gentle shaking of an oral suspension of meloxicam packaged in standard commercial glass bottles). The slowness of sedimentation ensures that the user has sufficient time to take homogeneous single doses of the oral suspension of a pharmaceutically active substance 15 according to the invention out of its primary packaging, thus ensuring accuracy of dosing. For example, an active substance suspension according to the invention contains 0.1 - 5 wt.% of highly dispersed 20 silicon dioxide (e.g. Aerosil® 200), preferably 0.5 - 2 wt.%, more particularly 0.5 - 1 wt.%. Suitable soluble hydrophilic polymers are pharmaceutical grade cellulose ethers such as hydroxyethyl cellulose 25 (HEC), hydroxypropyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC). Hydroxyethyl cellulose is preferred. For example, a suspension of active substance according to the invention contains 0.05 - 2 wt.% of water soluble cellulose ether, preferably 30 0.05 -0.5 wt.%, but more particularly 0.05 - 0.1 wt.%. Most preferably, the active substance suspension according to the invention contains 0.5 - 1 wt.% of highly dispersed silicon dioxide and 0.05 - 0.1 wt.% of hydroxyethyl 35 cellulose. - 8 - The properties of a liquid oral suspension of active substance according to the invention are greatly-influenced by the particle size of the suspended active substance. To achieve the rapid onset of activity which 5 is desirable when the preparation is taken once, a small particle size is essential, ensuring the fastest possible dissolution of the active substance in gastrointestinal tract. In the particle size spectrum of the active substance which is suitable for a suspension according to 10 the invention, therefore, at least 90% of the particles are smaller than 50 µm, preferably at least 50% of the particles are smaller than 10 µm, and most preferably about 90% of the particles are smaller than 10 µm (determined for example by laser diffractometry). A 15 correspondingly finely dispersed grade of pharmaceutical can easily be achieved by suitably grinding a coarser grade. Suitable mills for grinding operations of this kind are the standard commercial jet mills, for example. 20 The small particle size of the active substance in a suspension according to the invention as described also have the advantage of a slow rate of sedimentation of the suspended particles, which favourably affects the homogeneity of the liquid oral formulation of the active 25 substance described and correspondingly ensures a high degree of accuracy in measuring the dose. The solubility of the active substance in suitable physiologically acceptable dispersion media should be less 30 than 500 µg/ml. Preferably, the solubility is not more than 50 µg/ml, most preferably the solubility is not more than 5 µg/ml, but more particularly not more than 0.5 µg/ml. 35 it is readily possible for the skilled person to find, for any given active substance of the NSAID type, a suitable - 9 - physiologically acceptable dispersion medium in which the active substance has the solubility characteristics mentioned above. For meloxicam, the physiologically acceptable dispersion medium preferably consists of an 5 aqueous buffer system with a pH in the range from 2-4. An orally administered suspension according to the invention may contain one or more NSAID's as pharmaceutically active substance. The classic active 10 substance acetylsalicyclic acid and the active substances of the following categories are mentioned as examples of NSAID's: 15 20 (1) propionic acid derivatives, (2) acetic acid derivatives, (3) fenamic acid derivatives, (4) biphenylcarboxylic acid derivatives, (5) acid enolcarboxamides, (6) diaryl heterocycles with methylsulphonyl or aminosulphonyl substituents and (7) acid sulphonamides. The following active substances are mentioned as examples of propionic acid derivatives, although this list should 25 not be regarded as limiting this category of active substance: ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, 30 pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid and fluprofen or the pharmaceutically acceptable salts thereof. Examples of acetic acid derivatives include the following 35 active substances, although the list does not constitute any restriction of this category of active substance: - 10 - indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac and 5 oxpinac or the pharmaceutically acceptable salts thereof. The following active substances are mentioned as examples of fenamic acid derivatives, although the list does not constitute a limitation to this category of active 10 substance: mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid and tolfenamic acid or the pharmaceutically acceptable salts thereof. 15 Examples of biphenylcarboxylic acid derivatives include the following active substances, although the list does not constitute a limitation of this category of active substance: 20 diflunisal and flufenisal or the pharmaceutically acceptable salts thereof. The following are examples of acid enolcarboxamides 25 (oxicams), although the list does not constitute a restriction to this category of active substance: piroxicam, tenoxicam, lornoxicam and meloxicam or the pharmaceutically acceptable salts thereof. 30 Nimesulide is mentioned by way of example of an acid sulphonamide, but should not constitute a restriction to this category of active substances. 35 Chemical structures, pharmacological activity, side effects and information regarding the usual dosage ranges - 11 - for the above-mentioned NSAID's are given for example in Physician's Desk Reference, 35th Edition, 1981; The Merck Index, 12th Edition, Merck and Company, Rahway, New Jersey (1996); Cutting's Handbook of Pharmacology, 6th Edition, 5 Ed. T.Z. Czacky, M.D., Appleton-Century-Crofts, New York, 1979, Chapter 49:538-550. A dosage unit for the following NSAID's may be, for example: 10 100 - 500 mg diflunisal, 25 - 100 mg zomepirac sodium, 50 - 400 mg ibuprofen, 125 - 500 mg naproxen, 25 - 100 mg flurbiprofen, 50 - 100 mg fenoprofen, 10 - 20 mg piroxicam, 5 - 20 mg meloxicam, 125 - 250 mg mefenamic 15 acid, 100 - 400 mg fenbufen and 25 - 50 mg ketoprofen. Particularly preferred oral administered suspensions according to the invention are those which contain as active substance an acid enolcarboxamide, especially 20 meloxicam. Meloxicam is an NSAID with the structural type of an enolic acid and exhibits a distinctly pH-dependent solubility. The minimum solubility in buffered aqueous 25 systems is found at pH values from 2-4. The solubility in this pH range is less than 0.5 µg/ml (Luger P., Daneck K., Engel W., Trummlitz G., Wagner K., Structure and physicochemical properties of meloxicam, a new NSAID, Eur. J. Pharm. Sci. 4 (1996), 175-187). 30 Suitable dispersion media for a liquid oral suspension of meloxicam according to the invention are therefore physiologically acceptable aqueous buffer systems with a pH in the range from 2-4, mixtures thereof or mixtures 35 thereof with other physiologically acceptable liquids - 12 - which are additionally suitable for improving specific properties of the meloxicam suspension, especially • for adjusting the viscosity of the dispersion medium in 5 order to reduce the rate of sedimentation of the suspended particles of pharmaceutical, • to ensure that the liquid oral preparation has a pleasant flavour and • to improve the wetting qualities of the suspended 10 pharmaceutical particles. Other physiologically acceptable liquids in the sense of the invention described are preferably glycerol and optionally aqueous solutions of sugar alcohols such as 15 sorbitol, mannitol and xylitol, and mixtures thereof. In a suspension according to the invention these substances have the advantage • of increasing the viscosity of the dispersion medium 20 and hence reducing the rate of sedimentation of the suspended pharmaceutical particles and making it easier to handle when the liquid formulation is transferred into metering aids (e.g. standard measuring spoons or special metering systems), 25 • of their slightly sweet inherent flavour which gives the liquid oral formulation a pleasant taste, • of their suitability for diabetic patients and • of improving the wetting properties of the suspended pharmaceutical particles. 30 Suitable physiologically acceptable aqueous buffer systems with a pH in the range from 2-4 include, for example, sodium dihydrogen-phosphate dihydrate/citric acid monohydrate buffer, glycine/HCl (S. P. Sөrensen, Biochem. 35 Z., 21, 131 (1909); Biochem. Z., 22, 352 (1909)), Na- citrate/HCl (S. P. S0rensen, Biochem. Z., 21, 131 (1909); - 13 - Biochem. Z., 22, 352 (1909)), K-hydrogen phthalate/HCl (Clark and Lubs, J. Bact., 2, 1 (1917)), citric acid/phosphate (T. C. McIlvaine, J. Biol. Chem., 49, 183 (1921)), citrate-phosphate-borate/HCl (Teorell and 5 Stenhagen, Biochem. Z., 299, 416 (1938)) and Britton- Robinson Buffer (Britton and Welford, J. Chem. Soc., 1, 1848 (1937)). Preferably, a dispersion medium for a liquid oral 10 suspension of meloxicam according to the invention is based on an aqueous buffer system with a pH in the range from 2-4 mixed with one or more of the physiologically acceptable liquids glycerol and aqueous solutions of the sugar alcohols mannitol, sorbitol and xylitol. 15 For example, the dispersion medium of a liquid oral suspension of meloxicam according to the invention consists of mixtures of about 30-50% aqueous buffer system, pH 2-4, preferably aqueous sodium dihydrogen 20 phosphate dihydrate/citric acid monohydrate buffer, about 10-20% glycerol, about 10-20% xylitol and about 20-30% sorbitol or mannitol solution (70% sorbitol or mannitol in water). Glycerol and the above-mentioned sugar alcohols may be present either individually or in admixture with 25 one another in the dispersion medium. The suspension ready for use may contain varying amounts of the active substance meloxicam, e.g. 0.050 to 0.500 g/118 g, preferably 0.075 to 0.300 g/118 g, but 30 particularly 0.15 g/118 g, based on the mass of the preparation ready for use. To improve the flavour still further, one or more flavourings and/or one or more sweeteners may be added to 3 5 a liquid oral suspension according to the invention. - 14 - Suitable flavourings include, for example, liquid and powdered, water soluble natural and nature-identical flavourings. Particularly preferred are liquid flavourings, particularly raspberry, strawberry and honey. 5 Suitable sweeteners include, for example, saccharin sodium, saccharin, cyclamate, acesulfam potassium and taumatin. 10 Moreover, conventional excipients and/or preservatives effective in the pH range, i.e. preferably sodium benzoate in the case of the active substance meloxicam, may be added to a liquid oral suspension according to the invention. 15 Because of the three-dimensional siloid structure and the adhesion of the suspended solid particles, there is no need to add any surfactants to improve the wetting qualities. Surfactants may have a negative effect in 20 suspensions since the solubility of the solid in the dispersion medium may be increased in some cases, leading to an unwanted growth in particle size. Moreover, surfactants, particularly ionic surfactants, are frequently allergenic and/or irritant to the mucous 25 membranes. The invention further relates to a process for producing an orally administered liquid preparation of a pharmaceutically active substance of the NSAID type in the 30 form of a stabilised suspension, characterised in that (i) the solid active substance is ground in order to produce a particle size spectrum in which at least 90% of the particles are smaller than 50 µm, 35 preferably at least 50% of the particles are - 15 - smaller than 10 µm, but in particular about 90% of the particles are smaller than 10 µm, (ii) the ground active substance is suspended in a 5 physiologically inert dispersion medium in which the solubility of the active substance is very low, (iii) small amounts of highly dispersed silicon dioxide 10 are added to the dispersion medium with the application of high shear forces, (iv) small amounts of hydrophilic polymer soluble in the dispersion medium are added to the dispersion 15 medium and (v) optionally, one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may, independently of one another, 2 0 be added to the dispersion medium, the flavourings preferably being added during the final stage of manufacture owing to their foam breaking properties. 25 A preferred embodiment of the process according to the invention is characterised in that (i) a particle size spectrum is produced in which about 90% of the particles are smaller than 10 µm, 30 (ii) the ground active substance is suspended in a physiologically acceptable, aqueous buffer system at a pH in the range from 2-4, for example sodium dihydrogen phosphate dihydrate/citric acid 3 5 monohydrate buffer, glycine/HCl, K-hydrogen phthalate/HCl, citric acid/phosphate, citrate- - 16 - phosphate-borate/HCl or Britton-Robinson buffer, mixtures thereof with one another or mixtures thereof with other physiologically acceptable liquids such as glycerol or optionally aqueous 5 solutions of sugar alcohols such as sorbitol, mannitol and xylitol, (iii) with the aid of a mixer by the application of high shear forces, characterised for example by a 10 circumferential rotor speed of 15-35 m/s, preferably 20-30 m/s, 0.1-5.0 wt.-% of highly dispersed silicon dioxide, based on the weight of the suspension ready for use, are added to the dispersion medium, 15 (iv) water soluble cellulose ethers of pharmaceutical grade are added to the dispersion medium as hydrophilic polymers in an amount of from 0.05 - 2 wt.-%, based on the weight of the 20 suspension ready for use, and (v) one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may optionally be added 25 independently of one another to the dispersion medium. A particularly preferred embodiment of the process according to the invention is characterised in that 30 (i) a particle size spectrum is produced in which about 90% of the particles are smaller than 10 µm, (ii) the ground active substance is suspended in a 35 dispersion medium consisting of mixtures of 3 0 - 50% aqueous buffer systems with a pH in the - 17 - range from 2-4, aqueous sodium dihydrogen phosphate dihydrate/citric acid monohydrate buffer being preferred, 10-20% glycerol, 10-20% xylitol and 20-30% sorbitol or mannitol solution (70% 5 sorbitol or mannitol in water), whilst glycerol and the above-mentioned sugar alcohols may be present in the dispersion medium either individually or in admixture with one another, 10 (iii) 0.5-2.0 wt.-% of highly dispersed silicon dioxide, based on the weight of the suspension ready for use, are added to the dispersion medium with the aid of a mixer by applying high shear forces, characterised for example by a circumferential 15 rotor speed of 20 to 30 m/s, preferably about 25 to 27 m/s, (iv) pharmaceutical grade water-soluble cellulose ethers, preferably hydroxyethyl cellulose, are 20 added to the dispersion medium as hydrophilic polymers, in an amount of from 0.05 - 0.5 wt.-%, based on the weight of the suspension ready for use, and 25 (v) one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may optionally be added to the dispersion medium independently of one another. 3 0 In all the above-mentioned embodiments of the process, steps (ii) to (v) are preferably carried out in vacuo since the entry of air affects the density of the suspension to be produced, as a result of floating effects or air absorption on the siloid structure, and 3 5 inhomogeneities may be produced. - 18 - A particularly preferred embodiment of the process according to the invention is characterised in that the active substance is an acid enolcarboxamide, particularly meloxicam. 5 A third object of the invention is the use of an active substance of the NSAID type, preferably an acid enolcarboxamide, but particularly meloxicam, for preparing a liquid preparation of the active substance in the form 10 of a stabilised suspension with a particle size spectrum wherein at least 90% of the particles are smaller than 50 µm, in a physiologically inert dispersion medium in which the active substance has very low solubility, so that the suspension does not have any noticeable taste, 15 for oral administration, characterised in that the suspension contains a small amount of highly dispersed silicon dioxide for stabilising it by forming a three-dimensional siloid structure, the three-dimensional siloid structure being produced by adding the silicon dioxide to 2 0 the dispersion medium with the action of high shear forces, and the suspension additionally contains a small amount of hydrophilic polymer soluble in the dispersion medium. 5. Example The following recipe is for the preparation of 100 ml of a 30 liquid, orally administered suspension of meloxicam according to the invention. The formulation makes it possible to take several doses of 7.5 mg of meloxicam in a volume of 5 ml from a suitably sized glass bottle by pouring into standard plastic measuring spoons. The 35 ingredients which are relevant to the effectiveness and the formation of the siloid structure according to the - 19 - invention are given quantitatively, whilst all the other ingredients may be present in the formulation in accordance with the information provided above. 5 In order to protect it from microbial contamination during use (multi-dose container) the preparation must be suitably preserved with a preservative (in this case sodium benzoate) adapted to the pH range of the dispersion medium. Other ingredients are: 70% sorbitol solution (non-crystalline), 85% glycerol, 5 xylitol, sodium dihydrogen phosphate dihydrate, citric acid monohydrate, saccharin sodium crystals, sodium benzoate and raspberry flavouring D 9599. The mixture is made up to a final volume of 100 ml, corresponding to 118.000 g, with purified water. 0 5.1 Physical/chemical properties of the preparations pH: 3.5-4.5 5 Density: 1.16 - 1.20 g/ml (20°C) Viscosity: 40 - 150 mPas 5.2 Pharmacokinetic properties of the preparation - 20 - A main objective for developing a liquid oral formulation of meloxicam was the rapid onset of activity on first use. The prerequisite for this is the fastest possible flooding of the drug into the central blood compartment. 5 In the formulation according to the above Example this is achieved. In a direct comparison between a suspension according to the invention and a capsule containing the same dose, the time for maximum plasma concentration on a 10 single dose of meloxicam is tmax = 2h (1.5 - 5 h; suspension) as against tmax = 5h (2 - 6 h; capsule) . In the steady state, bioequivalence should be detectable owing to the desired therapeutic equivalents of the 15 suspension according to the invention and a solid oral formulation. This has been shown by direct comparison of a suspension according to the invention with a capsule containing the same dose. In the steady state the maximum plasma levels are at tmax (ss) = 5.0 h (5 - 9 h; suspension) 20 and tmax (ss) = 5.0 h (3 - 7 h; capsule) . A graphic representation of the results of the study is shown in Figure 2. 25 6. Method of preparation Suspensions according to the invention can be prepared by a multi-stage mixing and homogenising process. The use of shear-intensive homogenising mixers which enable the solid 30 particles of the active substance which are to be suspended and the highly dispersed silicon dioxide to be distributed in the dispersion medium within a very short time is crucial to the production of a homogeneous suspension having the siloid structure described. 35 Different sizes of process mixers from the series "Becomix" (made by Messrs. A. Berents GmbH & Co. KG, - 21 - Henleinstr. 19, D-28816 Stuhr) have proved particularly suitable for this purpose and will produce suspensions according to the invention in batch sizes ranging from 2.5 to 1,000 kg. These mixers incorporate fast rotating 5 homogenisers working on the rotor-stator principle which ensure optimum mixing and production of the three-dimensional siloid structure described above. Sufficiently high shear forces are generated, for example, at a circumferential rotor speed of 20 to 3 0 m/s, 10 preferably about 25 to 27 m/s. With the mixers Becomix RW 60/RW 1000, circumferential rotor speeds of about 26 m/s are used for about 10 - 15 minutes to introduce the highly dispersed silicon dioxide into the dispersing agent. 15 Step 1 (Premix) The active substance and the highly dispersed silicon dioxide are homogeneously premixed in a suitable container 20 (e.g. VA container). This premixing is necessary in order to achieve better wetting properties of the pharmaceutical substance and lump-free distribution in the suspension. 25 Step 2 (Polymer solution) The majority of the water is placed in a suitable batch container (e.g. Becomix mixer) and the HEC is sucked in with stirring, homogenisation and in vacuo and then the 3 0 mixture is stirred for about 10 minutes in vacuo. The HEC is allowed to swell for about 3 0 min. at room temperature (RT) before heating to about 80°C in vacuo and maintaining for about 1 hours at this temperature and cooling to RT again. 35 Step 3 (Sodium benzoate solution) - 22 - A small amount of the water is placed in a suitable batch container (e.g. VA container) and the sodium benzoate is dissolved therein with stirring. 5 Step 4 (Final mixing) The sodium benzoate solution (see above) and the other ingredients of the composition with the exception of the 10 flavouring are added to the polymer solution (sucked in under vacuum). The mixture is then homogenised. The mixture of active substance and silicon dioxide is then added in vacuo, with stirring and homogenisation and the mixture is homogenised for a further 10 minutes in vacuo. 15 The high shear forces described are characterised, for example, in that the mixture of active substance and silicon dioxide in a 1000 kg batch is sucked into the circulation in a mixer of the Becomix RW 1000 type at a rotor speed of about 3500 rpm (corresponding to a 20 circumferential speed of about 26 m/s) and then homogenised for 10 minutes. Finally, the flavouring is added in vacuo, with stirring and homogenisation. This method makes use of the foam-breaking properties of the flavouring, which shortens the subsequent process of de- 25 aerating the suspension (vacuum). The suspension can be transferred from the mixer into bulk containers under pressure. WE CLAIM: 1 Process for preparing an orally administered liquid preparation of a pharmaceutical active substance of the NSAID type in the form of a stabilised suspension, characterised in that (i) the solid active substance is ground in order to produce a particle size spectrum in which at least 90% of the particles are smaller than 50 µm, preferably at least 50% of the particles are smaller than 10 µm, but in particular about 90% of the particles are smaller than 10 µm; (ii) the ground active substance is suspended in a physiologically inert dispersion medium in which the solubility of the active substance is very low; (iii) 0.1 -5 wt.-% of highly dispersed silicon dioxide are added to the dispersion medium with the application of high shear forces; (iv) 0.05 to 2 wt.-% of hydrophilic polymer soluble in the dispersion medium' are added to the dispersion medium; and (v) optionally, one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may, independently of one another, be added to the dispersion medium, the flavourings preferably being added during the final stage of manufacture owing to their foam breaking properties. 2 Process as claimed in claim 1, wherein said suspension preferably contains 0.5-2 wt.-% of said highly dispersed silicon dioxide. 3 Process as claimed in claim 1 or 2, wherein said highly dispersed silicon dioxide has a specific surface area of at least 50 m2/g, preferably 100 to 400 m2/g. Process as claimed in claim 1, wherein said soluble hydrophilic polymer is selected from a group comprising a pharmaceutical-grade water soluble cellulose ether, preferably hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) or hydroxypropylmethyl cellulose (HPMC). Process as claimed in claim 1 or 4, wherein said soluble hydrophilic polymer is preferably taken in an amount of from 0.05-0.5 wt.-%. Process as claimed in claim 1, wherein said active substance is acetylsalicylic acid or an NSAID of one or more the following categories: a) a propionic acid derivative, preferably Ibuprofen, Naproxen, Flurbiprofen, Fenoprofen, Fenbufen, Ketoprofen, Indoprofen, Pirprofen, Carprofen, Oxaprozin, Pranoprofen, Miroprofen, Tioxaprofen, Suprofen, Alminoprofen, Tiaprofenic acid and Fluprofen or the pharmaceutically acceptable salts thereof, b) an acetic acid derivative, preferably Indomethacin, Sulindac, Tolmetin, Zomepirac, Nabumetone, Diclofenac, Fenclofenac, Alclofenac, Bromfenac, Ibufenac, Aceclofenac, Acemetacin, Fentiazac, Clidanac, Etodolac and Oxpinac or the pharmaceutically acceptable salts thereof, c) a fenamic acid derivative, preferably Mefenamic acid, Meclofenamic acid, Flufenamic acid, Niflumic acid and Tolfenamic acid or the pharmaceutically acceptable salts thereof, d) a biphenylcarboxylic acid derivative, preferably Diflunisal and Flufenisal or the pharmaceutically acceptable salts thereof, e) an acid enolcarboxamide, preferably Piroxicam, Tenoxicam, Lornoxicam and Meloxicam or the pharmaceutically acceptable salts thereof, f) a diaryl-heterocycle with methylsulphonyl- or aminosulphonyl substituents or a pharmaceutically acceptable salt thereof, g) an acid sulphonamide, preferably Nimesulide or a pharmaceutically acceptable salt thereof. 7 Process as claimed in claim 1, wherein said active substance meloxicam and said physiologically acceptable dispersion medium is an aqueous buffer system with a pH in the range from 2-4. 8 Process as claimed in claim 1 or 7, wherein said physiologically acceptable dispersion medium is a mixture of a physiologically acceptable aqueous buffer system with a pH in the range from 2-4 with other physiologically acceptable liquids, preferably with glycerol and/or optionally aqueous solutions of sugar alcohols such as sorbitol, mannitol and xylitol or mixtures thereof which are suitable for improving specific properties of the suspension. 9 Process as claimed in claim 7 or 8, wherein said physiologically acceptable dispersion medium is a buffer system selected from: a) sodium dihydrogen phosphate dihydrate/citric acid monohydrate, b) glycin/HCl, c) Na-citrate/HCl, d) K-hydrogen phthalate/HCl, e) citric acid/phosphate, f) citrate-phosphate-borate/HCl and g) Britton-Robinson buffer. 10 Process as claimed in claim 8, wherein said dispersion medium consists of a mixture of 30-50% aqueous sodium dihydrogen phosphate dihydrate/citric acid monohydrate buffer, 10-20% glycerol, 10-20% xylitol and 20-30% sorbitol or mannitol solution, the sorbitol or mannitol solution being a 70% aqueous solution. Process as claimed in claim 1, wherein said suspension contains as active substance 0.050 to 3.000 g/118 g of meloxicam, based on the mass of the preparation ready for use, and optionally one or more flavourings and/or one or more sweeteners and/or conventional excipients and/or preservatives which are effective at the pH range. Process as claimed in claim 1, wherein said active substance is an acid enolcarboxamide, preferably meloxicam, and (i) a particle size spectrum is produced in which about 90% of the particles are smaller than 10 µm, (ii) the ground active substance is suspended in a physiologically acceptable, aqueous buffer system at a pH in the range from 2-4, for example sodium dihydrogen phosphate dihydrate/citric acid monohydrate buffer, glycine/HC1, K-hydrogen phthalate/HCl, citric acid/phosphate, citrate-phosphate-borate/HCl or Britton-Robinson buffer, mixtures thereof with one another or mixtures thereof with other physiologically acceptable liquids such as glycerol or optionally aqueous solutions of sugar alcohols such as sorbitol, mannitol and xylitol, (iii) with the aid of a mixer by the application of high shear forces, characterized for example by a circumferential rotor speed of 15 to 35 m/s, preferably 20 to 30 m/s, 0.1-5.0 wt.-% of highly dispersed silicon dioxide, based on the weight of the suspension ready for use, are added to the dispersion medium, (iv) water soluble cellulose ethers of pharmaceutical grade, preferably hydroxyethylcellulose are added to the dispersion medium as hydrophilic polymers in an amount of from 0.05 - 2 wt.-%, based on the weight of the suspension ready for use, and (v) one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may optionally be added independently of one another to the dispersion medium. Dated this 4th day of August, 2000. i [Dr. Ramesh Kumar Mehta] of Remfry & Sagar -7- Attorney for the Applicants

Full Text

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
COMPLETE SPECIFICATION
[See Section 10; rule 13]]
"PROCESS FOR PREPARING AN ORALLY ADMINISTERED LIQUID PREPARATION"
BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG. (formerly known as BOEHRINGER INGELHEIM PHARMA KG.), a German company, of Binger Strasse 173, D-55216 Ingelheim am Rhein, Germany.
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-

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S018-543J.pri
Boehringer Ingelheim Pharma KG Case 5/1232-Ro
D-55216 Ingelheim 5
Oral Suspension of Active Substance
10 1. Introduction
The present invention relates to orally administered suspensions of pharmaceutically active substances of the NSAID type (nonsteroidal-antiinflammatory drugs), but 15 particularly the antirheumatic agent meloxicam and a process for preparing them.
2. Statement of Problem
20 Various pharmaceutical forms are used for oral
administration of drugs. Thus, in addition to solid single-dose forms such as tablets, hard and soft gelatine capsules, liquid forms such as solutions and syrups are also given, in which the dose to be administered can be
25 adjusted by means of the volume given.
Solutions and syrups have the advantage that they can be taken easily and safely even by patients who have trouble taking solid, single-dose forms (e.g. children and older 30 patients).
However, it should be borne in mind that even with the same dosage and the same method of administration, the activity of the same pharmaceutical substance may vary. 35 These variations mean that the therapeutic effect clinically demonstrated for a drug in a specific

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preparation cannot be achieved with a different preparation of the same drug, and furthermore within a course of treatment one preparation cannot readily be exchanged for another. Preparations which are not 5 therapeutically equivalent are known as "non-bioequivalent". For the oral administration of pharmaceutical preparations, the drug is usually absorbed faster from liquid preparations, particularly solutions, than from tablets or capsules and these drugs are 10 consequently not always bioequivalent (Bauer K. H.;
Fromming K.-H.; Fuhrer C, Pharmazeutische Technologie, 5th Edition 1997, Gustav Fischer Verlag, Stuttgart, page 213) .
15 Meloxicam is an antirheumatic agent belonging to the
NSAID's. NSAID's are cyclooxygenase inhibitors, whilst meloxicam has been shown to have a selective inhibitory effect on the isoenzyme COX-2 and consequently a reduced risk of undesirable gastrointestinal side effects. For
20 safe administration of meloxicam and other active
substances, e.g. other NSAID's, a liquid oral preparation is desirable as an alternative to the solid form (capsule, tablet), particularly in paediatrics.
25 The complex objective of the present invention was primarily to produce an orally administered liquid preparation of meloxicam. The formulation should take effect rapidly when first used in acute cases. However, the substance is preferably used for long-term therapy.
30 In such long-term therapy, the liquid oral formulation should be bioequivalent to other oral formulations (tablet, capsule) in the steady state in order to allow therapy with either a liquid or solid oral formulation as desired. At the same time, the liquid preparation should
35 have a pleasant flavour in order to be acceptable to
children and thus ensure that it is taken as specified and

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the treatment is ensured. In addition, the liquid preparation should preferably not contain any ethanol, since the possibility of ethanol having a harmful effect even in physiologically acceptable, non-toxic 5 concentrations cannot be ruled out completely,
particularly in children. Moreover, when ethanol is used, there is the risk of abuse by alcohol-dependent patients or relapse on the part of formerly alcohol-dependent patients. The suitability of the formulation for diabetic
10 patients should also be taken into account. To ensure exact dosage of a liquid oral preparation of meloxicam, the preparation should also be homogeneous over a sufficient length of time during its removal from the primary packaging.
15
3. Specification of the Invention
One obvious way of preparing a liquid oral formulation of 20 a pharmaceutically active substance is to dissolve the substance in physiologically inert solvents (especially pharmaceutical grade water). However, this approach is unsuitable in many cases. To ensure the desired pleasant taste of a liquid oral formulation, e.g. meloxicam, it is 25 not possible to use solutions, since the substance in the dissolved state has an unpleasant taste of its own. This taste is apparent in all the solvents which can be used for the oral administration of solutions and cannot be adequately masked even by the addition of flavour 30 correcting agents such as flavourings and sweeteners.
However, meloxicam does not have a noticeable flavour of its own when the substance is suspended in a physiologically inert dispersion medium for a liquid oral 3 5 preparation and the solubility of meloxicam in the
dispersion medium used is very slight. This provided a

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suitable approach to solving the problem. This approach can be applied analogously to other active substances of the NSAID category. Since a clearly noticeable unpleasant taste is present even at a concentration of over 500 µg/ml 5 of dissolved meloxicam, the solubility of this active
substance in the dispersion media used must be below this threshold.
When a suspension of active substance is used there is the
10 problem that the homogeneity of the suspension has to be ensured for a sufficient length of time during removal from the primary packaging (e.g. glass bottle, 100 ml) to ensure accurate dosing. However, the sedimentation of solids dispersed in liquid media cannot be prevented but
15 only delayed for a greater or lesser period. One
conventional approach to delaying sedimentation is, for example, by increasing the viscosity of the dispersing medium by the addition of suitable substances, e.g. organic hydrocolloid forming agents, e.g. cellulose ether,
20 or silicon dioxide as a thickener. Increasing the
viscosity of the dispersing agent does, however, have the serious disadvantage that it makes it considerably more difficult to redisperse the sediment formed, to the extent that if the suspension is too viscous it is impossible to
25 reconstitute the suspension at all. Moreover, the caking caused by contact of the individual particles under the effects of gravity during storage of the suspension must be avoided. It is known from the literature to prevent caking by, for example, controlled flocculation of such
3 0 systems by the adsorption of potential-determining ions (Sucker H., Fuchs P., Speiser P., Pharmazeutische Technologie, 5th Edition 1991, Georg Thieme Verlag, Stuttgart, p. 423). The industrial manufacture of stable suspensions by controlled flocculation is subject to
35 limitations, since it is difficult to reproduce the
optimum properties of suspension systems of this kind

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owing to the variability of the suspended solid and the stability of the suspension is considerably affected by the adjuvants used.
5 Surprisingly, the suspension of a pharmaceutically active substance of the NSAID type can be stabilised by the addition of small amounts of highly dispersed silicone dioxide in the presence of small amounts of hydrophilic polymers. Because of the low concentration of highly
10 dispersed silicon dioxide and hydrophilic polymer in the dispersion medium, the viscosity is low; unwanted increased in viscosity, which will prevent reconstitution of the suspension, caused by gel-like thickening of the dispersion medium does not occur if at the same time small
15 amounts of hydrophilic polymer which are soluble in the
dispersion medium are added to the medium and the silicon dioxide is added to the suspension with the aid of high shear forces. Suitably high shear forces can be produced with a suitable shear-intensive homogenising mixer, e.g.
20 with mixers of the series "Becomix" made by Messrs. A. Berents GmbH & Co. KG, Henleinstr. 19, D-28816 Stuhr, which comprise rapidly rotating homogenisers working on the rotor-stator principle. A circumferential rotor speed of about 25 to 27 m/s is particularly suitable for
25 generating sufficiently high shear forces and is used to introduce the highly dispersed silicon dioxide into the dispersing agent for about 10 - 15 minutes, e.g. using the mixers Becomix RW 60/RW 1000. This produces a special siloid structure which consists of a spongy three-
3 0 dimensional structure of hydratised highly dispersed
silicon dioxide shot through with cavities, the active substance being adsorbed onto said structure.
Suitable highly dispersed silicon dioxide has a specific 35 surface area of at least 50 m2/g/ preferably 100 to
400 m2/g, for example, whilst a specific surface area of

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about 200 m2/g is particularly preferred (e.g. Aerosil® 200) .
The invention relates to a suspension of a 5 pharmaceutically active substance of the NSAID type with suspendable particle size spectrum in a physiologically inert dispersion medium in which the active substance has very little solubility, so that the suspension has no perceptible taste of its own, for oral administration,
10 characterised in that the suspension contains a small amount of highly dispersed silicon dioxide for stabilisation by forming a three-dimensional siloid structure, the three-dimensional siloid structure being produced by adding the silicon dioxide to the dispersion
15 medium under the action of high shear forces, and the suspension additionally contains a small amount of hydrophilic polymer which is soluble in the dispersion medium.
20 The above-mentioned three-dimensional siloid structure
consists of crosslinked, swollen and coherent strands of SiO2 between which can be found fairly large cavities filled with dispersion medium. The suspended solid particles of the active substance, e.g. meloxicam, are
25 adsorbed almost exclusively onto the SiO2 strands. In this way, the suspended particles are rapidly and fully wetted and agglomeration of the particles of pharmaceutical substance can be prevented entirely. This results in a suspension of the active substance of
30 exceptional homogeneity and dosing precision. The siloid structure described does not lead to any gel-like thickening of the dispersion medium but rather produces a low viscosity pourable suspension. Figure 1 illustrates the siloid structure described.

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At the same time, the three-dimensional siloid structure acts as a sedimentation stabiliser. The structure described is very bulky and is compressed only slightly and very slowly even by sedimentation. Thus, even after 5 months of storage, the volume of the siloid structure decreases by only about 20%. The reduction in volume caused by sedimentation does not result in undesirable caking; the sediment can be easily and quickly redispersed by the use of extremely slight mechanical forces (e.g.
10 very gentle shaking of an oral suspension of meloxicam packaged in standard commercial glass bottles). The slowness of sedimentation ensures that the user has sufficient time to take homogeneous single doses of the oral suspension of a pharmaceutically active substance
15 according to the invention out of its primary packaging, thus ensuring accuracy of dosing.
For example, an active substance suspension according to the invention contains 0.1 - 5 wt.% of highly dispersed 20 silicon dioxide (e.g. Aerosil® 200), preferably 0.5 - 2 wt.%, more particularly 0.5 - 1 wt.%.
Suitable soluble hydrophilic polymers are pharmaceutical grade cellulose ethers such as hydroxyethyl cellulose
25 (HEC), hydroxypropyl cellulose (HPC) and
hydroxypropylmethyl cellulose (HPMC). Hydroxyethyl cellulose is preferred. For example, a suspension of active substance according to the invention contains 0.05 - 2 wt.% of water soluble cellulose ether, preferably
30 0.05 -0.5 wt.%, but more particularly 0.05 - 0.1 wt.%.
Most preferably, the active substance suspension according to the invention contains 0.5 - 1 wt.% of highly dispersed silicon dioxide and 0.05 - 0.1 wt.% of hydroxyethyl 35 cellulose.

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The properties of a liquid oral suspension of active substance according to the invention are greatly-influenced by the particle size of the suspended active substance. To achieve the rapid onset of activity which 5 is desirable when the preparation is taken once, a small particle size is essential, ensuring the fastest possible dissolution of the active substance in gastrointestinal tract. In the particle size spectrum of the active substance which is suitable for a suspension according to
10 the invention, therefore, at least 90% of the particles are smaller than 50 µm, preferably at least 50% of the particles are smaller than 10 µm, and most preferably about 90% of the particles are smaller than 10 µm (determined for example by laser diffractometry). A
15 correspondingly finely dispersed grade of pharmaceutical can easily be achieved by suitably grinding a coarser grade. Suitable mills for grinding operations of this kind are the standard commercial jet mills, for example.
20 The small particle size of the active substance in a
suspension according to the invention as described also have the advantage of a slow rate of sedimentation of the suspended particles, which favourably affects the homogeneity of the liquid oral formulation of the active
25 substance described and correspondingly ensures a high degree of accuracy in measuring the dose.
The solubility of the active substance in suitable physiologically acceptable dispersion media should be less 30 than 500 µg/ml. Preferably, the solubility is not more
than 50 µg/ml, most preferably the solubility is not more than 5 µg/ml, but more particularly not more than 0.5 µg/ml.
35 it is readily possible for the skilled person to find, for any given active substance of the NSAID type, a suitable

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physiologically acceptable dispersion medium in which the active substance has the solubility characteristics mentioned above. For meloxicam, the physiologically acceptable dispersion medium preferably consists of an 5 aqueous buffer system with a pH in the range from 2-4.
An orally administered suspension according to the invention may contain one or more NSAID's as pharmaceutically active substance. The classic active 10 substance acetylsalicyclic acid and the active substances of the following categories are mentioned as examples of NSAID's:
15
20
(1) propionic acid derivatives,
(2) acetic acid derivatives,
(3) fenamic acid derivatives,
(4) biphenylcarboxylic acid derivatives,
(5) acid enolcarboxamides,
(6) diaryl heterocycles with methylsulphonyl or aminosulphonyl substituents and
(7) acid sulphonamides.
The following active substances are mentioned as examples of propionic acid derivatives, although this list should 25 not be regarded as limiting this category of active substance:
ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, 30 pranoprofen, miroprofen, tioxaprofen, suprofen,
alminoprofen, tiaprofenic acid and fluprofen or the pharmaceutically acceptable salts thereof.
Examples of acetic acid derivatives include the following 35 active substances, although the list does not constitute any restriction of this category of active substance:

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indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac and 5 oxpinac or the pharmaceutically acceptable salts thereof.
The following active substances are mentioned as examples of fenamic acid derivatives, although the list does not constitute a limitation to this category of active 10 substance:
mefenamic acid, meclofenamic acid, flufenamic acid,
nifluminic acid and tolfenamic acid or the
pharmaceutically acceptable salts thereof. 15
Examples of biphenylcarboxylic acid derivatives include
the following active substances, although the list does
not constitute a limitation of this category of active
substance: 20
diflunisal and flufenisal or the pharmaceutically
acceptable salts thereof.
The following are examples of acid enolcarboxamides 25 (oxicams), although the list does not constitute a restriction to this category of active substance:
piroxicam, tenoxicam, lornoxicam and meloxicam or the pharmaceutically acceptable salts thereof. 30
Nimesulide is mentioned by way of example of an acid sulphonamide, but should not constitute a restriction to this category of active substances.
35 Chemical structures, pharmacological activity, side
effects and information regarding the usual dosage ranges

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for the above-mentioned NSAID's are given for example in Physician's Desk Reference, 35th Edition, 1981; The Merck Index, 12th Edition, Merck and Company, Rahway, New Jersey (1996); Cutting's Handbook of Pharmacology, 6th Edition, 5 Ed. T.Z. Czacky, M.D., Appleton-Century-Crofts, New York, 1979, Chapter 49:538-550.
A dosage unit for the following NSAID's may be, for example:
10
100 - 500 mg diflunisal, 25 - 100 mg zomepirac sodium, 50 - 400 mg ibuprofen, 125 - 500 mg naproxen, 25 - 100 mg flurbiprofen, 50 - 100 mg fenoprofen, 10 - 20 mg piroxicam, 5 - 20 mg meloxicam, 125 - 250 mg mefenamic
15 acid, 100 - 400 mg fenbufen and 25 - 50 mg ketoprofen.
Particularly preferred oral administered suspensions according to the invention are those which contain as active substance an acid enolcarboxamide, especially 20 meloxicam.
Meloxicam is an NSAID with the structural type of an enolic acid and exhibits a distinctly pH-dependent solubility. The minimum solubility in buffered aqueous
25 systems is found at pH values from 2-4. The solubility in this pH range is less than 0.5 µg/ml (Luger P., Daneck K., Engel W., Trummlitz G., Wagner K., Structure and physicochemical properties of meloxicam, a new NSAID, Eur. J. Pharm. Sci. 4 (1996), 175-187).
30
Suitable dispersion media for a liquid oral suspension of meloxicam according to the invention are therefore physiologically acceptable aqueous buffer systems with a pH in the range from 2-4, mixtures thereof or mixtures
35 thereof with other physiologically acceptable liquids

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which are additionally suitable for improving specific properties of the meloxicam suspension, especially
• for adjusting the viscosity of the dispersion medium in
5 order to reduce the rate of sedimentation of the
suspended particles of pharmaceutical,
• to ensure that the liquid oral preparation has a
pleasant flavour and
• to improve the wetting qualities of the suspended
10 pharmaceutical particles.
Other physiologically acceptable liquids in the sense of the invention described are preferably glycerol and optionally aqueous solutions of sugar alcohols such as 15 sorbitol, mannitol and xylitol, and mixtures thereof. In a suspension according to the invention these substances have the advantage
• of increasing the viscosity of the dispersion medium
20 and hence reducing the rate of sedimentation of the
suspended pharmaceutical particles and making it easier to handle when the liquid formulation is transferred into metering aids (e.g. standard measuring spoons or special metering systems), 25 • of their slightly sweet inherent flavour which gives the liquid oral formulation a pleasant taste,
• of their suitability for diabetic patients and
• of improving the wetting properties of the suspended
pharmaceutical particles.
30
Suitable physiologically acceptable aqueous buffer systems with a pH in the range from 2-4 include, for example, sodium dihydrogen-phosphate dihydrate/citric acid monohydrate buffer, glycine/HCl (S. P. Sөrensen, Biochem.
35 Z., 21, 131 (1909); Biochem. Z., 22, 352 (1909)), Na-
citrate/HCl (S. P. S0rensen, Biochem. Z., 21, 131 (1909);

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Biochem. Z., 22, 352 (1909)), K-hydrogen phthalate/HCl (Clark and Lubs, J. Bact., 2, 1 (1917)), citric
acid/phosphate (T. C. McIlvaine, J. Biol. Chem., 49, 183 (1921)), citrate-phosphate-borate/HCl (Teorell and 5 Stenhagen, Biochem. Z., 299, 416 (1938)) and Britton-
Robinson Buffer (Britton and Welford, J. Chem. Soc., 1,
1848 (1937)).
Preferably, a dispersion medium for a liquid oral
10 suspension of meloxicam according to the invention is
based on an aqueous buffer system with a pH in the range from 2-4 mixed with one or more of the physiologically acceptable liquids glycerol and aqueous solutions of the sugar alcohols mannitol, sorbitol and xylitol.
15
For example, the dispersion medium of a liquid oral suspension of meloxicam according to the invention consists of mixtures of about 30-50% aqueous buffer system, pH 2-4, preferably aqueous sodium dihydrogen
20 phosphate dihydrate/citric acid monohydrate buffer, about 10-20% glycerol, about 10-20% xylitol and about 20-30% sorbitol or mannitol solution (70% sorbitol or mannitol in water). Glycerol and the above-mentioned sugar alcohols may be present either individually or in admixture with
25 one another in the dispersion medium.
The suspension ready for use may contain varying amounts of the active substance meloxicam, e.g. 0.050 to 0.500 g/118 g, preferably 0.075 to 0.300 g/118 g, but 30 particularly 0.15 g/118 g, based on the mass of the preparation ready for use.
To improve the flavour still further, one or more flavourings and/or one or more sweeteners may be added to 3 5 a liquid oral suspension according to the invention.

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Suitable flavourings include, for example, liquid and powdered, water soluble natural and nature-identical flavourings. Particularly preferred are liquid flavourings, particularly raspberry, strawberry and honey. 5
Suitable sweeteners include, for example, saccharin sodium, saccharin, cyclamate, acesulfam potassium and taumatin.
10 Moreover, conventional excipients and/or preservatives
effective in the pH range, i.e. preferably sodium benzoate in the case of the active substance meloxicam, may be added to a liquid oral suspension according to the invention.
15
Because of the three-dimensional siloid structure and the adhesion of the suspended solid particles, there is no need to add any surfactants to improve the wetting qualities. Surfactants may have a negative effect in
20 suspensions since the solubility of the solid in the
dispersion medium may be increased in some cases, leading to an unwanted growth in particle size. Moreover, surfactants, particularly ionic surfactants, are frequently allergenic and/or irritant to the mucous
25 membranes.
The invention further relates to a process for producing
an orally administered liquid preparation of a
pharmaceutically active substance of the NSAID type in the
30 form of a stabilised suspension, characterised in that
(i) the solid active substance is ground in order to
produce a particle size spectrum in which at least
90% of the particles are smaller than 50 µm,
35 preferably at least 50% of the particles are

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smaller than 10 µm, but in particular about 90% of the particles are smaller than 10 µm,
(ii) the ground active substance is suspended in a
5 physiologically inert dispersion medium in which
the solubility of the active substance is very low,
(iii) small amounts of highly dispersed silicon dioxide
10 are added to the dispersion medium with the
application of high shear forces,
(iv) small amounts of hydrophilic polymer soluble in
the dispersion medium are added to the dispersion
15 medium and
(v) optionally, one or more flavourings, one or more
sweeteners, conventional excipients or one or more preservatives may, independently of one another,
2 0 be added to the dispersion medium, the flavourings
preferably being added during the final stage of manufacture owing to their foam breaking properties.
25 A preferred embodiment of the process according to the invention is characterised in that
(i) a particle size spectrum is produced in which
about 90% of the particles are smaller than 10 µm, 30
(ii) the ground active substance is suspended in a
physiologically acceptable, aqueous buffer system at a pH in the range from 2-4, for example sodium dihydrogen phosphate dihydrate/citric acid
3 5 monohydrate buffer, glycine/HCl, K-hydrogen
phthalate/HCl, citric acid/phosphate, citrate-

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phosphate-borate/HCl or Britton-Robinson buffer,
mixtures thereof with one another or mixtures
thereof with other physiologically acceptable
liquids such as glycerol or optionally aqueous
5 solutions of sugar alcohols such as sorbitol,
mannitol and xylitol,
(iii) with the aid of a mixer by the application of high shear forces, characterised for example by a
10 circumferential rotor speed of 15-35 m/s,
preferably 20-30 m/s, 0.1-5.0 wt.-% of highly dispersed silicon dioxide, based on the weight of the suspension ready for use, are added to the dispersion medium,
15
(iv) water soluble cellulose ethers of pharmaceutical grade are added to the dispersion medium as hydrophilic polymers in an amount of from 0.05 - 2 wt.-%, based on the weight of the
20 suspension ready for use, and
(v) one or more flavourings, one or more sweeteners,
conventional excipients or one or more
preservatives may optionally be added
25 independently of one another to the dispersion
medium.
A particularly preferred embodiment of the process according to the invention is characterised in that 30
(i) a particle size spectrum is produced in which
about 90% of the particles are smaller than 10 µm,
(ii) the ground active substance is suspended in a
35 dispersion medium consisting of mixtures of
3 0 - 50% aqueous buffer systems with a pH in the

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range from 2-4, aqueous sodium dihydrogen
phosphate dihydrate/citric acid monohydrate buffer
being preferred, 10-20% glycerol, 10-20% xylitol
and 20-30% sorbitol or mannitol solution (70%
5 sorbitol or mannitol in water), whilst glycerol
and the above-mentioned sugar alcohols may be present in the dispersion medium either individually or in admixture with one another,
10 (iii) 0.5-2.0 wt.-% of highly dispersed silicon dioxide, based on the weight of the suspension ready for use, are added to the dispersion medium with the aid of a mixer by applying high shear forces, characterised for example by a circumferential
15 rotor speed of 20 to 30 m/s, preferably about 25
to 27 m/s,
(iv) pharmaceutical grade water-soluble cellulose
ethers, preferably hydroxyethyl cellulose, are
20 added to the dispersion medium as hydrophilic
polymers, in an amount of from 0.05 - 0.5 wt.-%, based on the weight of the suspension ready for use, and
25 (v) one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may optionally be added to the dispersion medium independently of one another.
3 0 In all the above-mentioned embodiments of the process, steps (ii) to (v) are preferably carried out in vacuo since the entry of air affects the density of the suspension to be produced, as a result of floating effects or air absorption on the siloid structure, and
3 5 inhomogeneities may be produced.

- 18 -
A particularly preferred embodiment of the process according to the invention is characterised in that the active substance is an acid enolcarboxamide, particularly meloxicam. 5
A third object of the invention is the use of an active substance of the NSAID type, preferably an acid enolcarboxamide, but particularly meloxicam, for preparing a liquid preparation of the active substance in the form
10 of a stabilised suspension with a particle size spectrum wherein at least 90% of the particles are smaller than 50 µm, in a physiologically inert dispersion medium in which the active substance has very low solubility, so that the suspension does not have any noticeable taste,
15 for oral administration, characterised in that the
suspension contains a small amount of highly dispersed silicon dioxide for stabilising it by forming a three-dimensional siloid structure, the three-dimensional siloid structure being produced by adding the silicon dioxide to
2 0 the dispersion medium with the action of high shear
forces, and the suspension additionally contains a small amount of hydrophilic polymer soluble in the dispersion medium.
5. Example
The following recipe is for the preparation of 100 ml of a 30 liquid, orally administered suspension of meloxicam
according to the invention. The formulation makes it possible to take several doses of 7.5 mg of meloxicam in a volume of 5 ml from a suitably sized glass bottle by pouring into standard plastic measuring spoons. The 35 ingredients which are relevant to the effectiveness and the formation of the siloid structure according to the

- 19 -
invention are given quantitatively, whilst all the other ingredients may be present in the formulation in accordance with the information provided above.
5 In order to protect it from microbial contamination during use (multi-dose container) the preparation must be suitably preserved with a preservative (in this case sodium benzoate) adapted to the pH range of the dispersion medium.

Other ingredients are:
70% sorbitol solution (non-crystalline), 85% glycerol,
5 xylitol, sodium dihydrogen phosphate dihydrate, citric
acid monohydrate, saccharin sodium crystals, sodium
benzoate and raspberry flavouring D 9599. The mixture is
made up to a final volume of 100 ml, corresponding to
118.000 g, with purified water.
0
5.1 Physical/chemical properties of the preparations
pH: 3.5-4.5 5 Density: 1.16 - 1.20 g/ml (20°C) Viscosity: 40 - 150 mPas
5.2 Pharmacokinetic properties of the preparation

- 20 -
A main objective for developing a liquid oral formulation of meloxicam was the rapid onset of activity on first use. The prerequisite for this is the fastest possible flooding of the drug into the central blood compartment. 5
In the formulation according to the above Example this is achieved. In a direct comparison between a suspension according to the invention and a capsule containing the same dose, the time for maximum plasma concentration on a 10 single dose of meloxicam is tmax = 2h (1.5 - 5 h;
suspension) as against tmax = 5h (2 - 6 h; capsule) .
In the steady state, bioequivalence should be detectable owing to the desired therapeutic equivalents of the
15 suspension according to the invention and a solid oral
formulation. This has been shown by direct comparison of a suspension according to the invention with a capsule containing the same dose. In the steady state the maximum plasma levels are at tmax (ss) = 5.0 h (5 - 9 h; suspension)
20 and tmax (ss) = 5.0 h (3 - 7 h; capsule) . A graphic
representation of the results of the study is shown in Figure 2.
25 6. Method of preparation
Suspensions according to the invention can be prepared by a multi-stage mixing and homogenising process. The use of shear-intensive homogenising mixers which enable the solid
30 particles of the active substance which are to be
suspended and the highly dispersed silicon dioxide to be distributed in the dispersion medium within a very short time is crucial to the production of a homogeneous suspension having the siloid structure described.
35 Different sizes of process mixers from the series
"Becomix" (made by Messrs. A. Berents GmbH & Co. KG,

- 21 -
Henleinstr. 19, D-28816 Stuhr) have proved particularly suitable for this purpose and will produce suspensions according to the invention in batch sizes ranging from 2.5 to 1,000 kg. These mixers incorporate fast rotating 5 homogenisers working on the rotor-stator principle which ensure optimum mixing and production of the three-dimensional siloid structure described above. Sufficiently high shear forces are generated, for example, at a circumferential rotor speed of 20 to 3 0 m/s,
10 preferably about 25 to 27 m/s. With the mixers Becomix RW 60/RW 1000, circumferential rotor speeds of about 26 m/s are used for about 10 - 15 minutes to introduce the highly dispersed silicon dioxide into the dispersing agent.
15
Step 1 (Premix)
The active substance and the highly dispersed silicon dioxide are homogeneously premixed in a suitable container 20 (e.g. VA container). This premixing is necessary in order to achieve better wetting properties of the pharmaceutical substance and lump-free distribution in the suspension.
25 Step 2 (Polymer solution)
The majority of the water is placed in a suitable batch container (e.g. Becomix mixer) and the HEC is sucked in with stirring, homogenisation and in vacuo and then the 3 0 mixture is stirred for about 10 minutes in vacuo. The HEC is allowed to swell for about 3 0 min. at room temperature (RT) before heating to about 80°C in vacuo and maintaining for about 1 hours at this temperature and cooling to RT again.
35
Step 3 (Sodium benzoate solution)

- 22 -
A small amount of the water is placed in a suitable batch container (e.g. VA container) and the sodium benzoate is dissolved therein with stirring. 5
Step 4 (Final mixing)
The sodium benzoate solution (see above) and the other ingredients of the composition with the exception of the
10 flavouring are added to the polymer solution (sucked in under vacuum). The mixture is then homogenised. The mixture of active substance and silicon dioxide is then added in vacuo, with stirring and homogenisation and the mixture is homogenised for a further 10 minutes in vacuo.
15 The high shear forces described are characterised, for example, in that the mixture of active substance and silicon dioxide in a 1000 kg batch is sucked into the circulation in a mixer of the Becomix RW 1000 type at a rotor speed of about 3500 rpm (corresponding to a
20 circumferential speed of about 26 m/s) and then
homogenised for 10 minutes. Finally, the flavouring is added in vacuo, with stirring and homogenisation. This method makes use of the foam-breaking properties of the flavouring, which shortens the subsequent process of de-
25 aerating the suspension (vacuum). The suspension can be transferred from the mixer into bulk containers under pressure.

WE CLAIM:
1 Process for preparing an orally administered liquid preparation of a pharmaceutical active substance of the NSAID type in the form of a stabilised suspension, characterised in that (i) the solid active substance is ground in order to produce a particle size spectrum in which at least 90% of the particles are smaller than 50 µm, preferably at least 50% of the particles are smaller than 10 µm, but in particular about 90% of the particles are smaller than 10 µm; (ii) the ground active substance is suspended in a physiologically inert dispersion medium in which the solubility of the active substance is very low; (iii) 0.1 -5 wt.-% of highly dispersed silicon dioxide are added to the dispersion medium with the application of high shear forces; (iv) 0.05 to 2 wt.-% of hydrophilic polymer soluble in the dispersion medium' are added to the dispersion medium; and (v) optionally, one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may, independently of one another, be added to the dispersion medium, the flavourings preferably being added during the final stage of manufacture owing to their foam breaking properties.
2 Process as claimed in claim 1, wherein said suspension preferably contains 0.5-2 wt.-% of said highly dispersed silicon dioxide.
3 Process as claimed in claim 1 or 2, wherein said highly dispersed silicon dioxide has a specific surface area of at least 50 m2/g, preferably 100 to 400 m2/g.

Process as claimed in claim 1, wherein said soluble hydrophilic polymer is selected from a group comprising a pharmaceutical-grade water soluble cellulose ether, preferably hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) or hydroxypropylmethyl cellulose (HPMC).
Process as claimed in claim 1 or 4, wherein said soluble hydrophilic polymer is preferably taken in an amount of from 0.05-0.5 wt.-%.
Process as claimed in claim 1, wherein said active substance is acetylsalicylic acid or an NSAID of one or more the following categories:
a) a propionic acid derivative, preferably Ibuprofen, Naproxen, Flurbiprofen, Fenoprofen, Fenbufen, Ketoprofen, Indoprofen, Pirprofen, Carprofen, Oxaprozin, Pranoprofen, Miroprofen, Tioxaprofen, Suprofen, Alminoprofen, Tiaprofenic acid and Fluprofen or the pharmaceutically acceptable salts thereof,
b) an acetic acid derivative, preferably Indomethacin, Sulindac, Tolmetin, Zomepirac, Nabumetone, Diclofenac, Fenclofenac, Alclofenac, Bromfenac, Ibufenac, Aceclofenac, Acemetacin, Fentiazac, Clidanac, Etodolac and Oxpinac or the pharmaceutically acceptable salts thereof,
c) a fenamic acid derivative, preferably Mefenamic acid, Meclofenamic acid, Flufenamic acid, Niflumic acid and Tolfenamic acid or the pharmaceutically acceptable salts thereof,
d) a biphenylcarboxylic acid derivative, preferably Diflunisal and Flufenisal or the pharmaceutically acceptable salts thereof,
e) an acid enolcarboxamide, preferably Piroxicam, Tenoxicam, Lornoxicam and Meloxicam or the pharmaceutically acceptable salts thereof,

f) a diaryl-heterocycle with methylsulphonyl- or aminosulphonyl substituents or a pharmaceutically acceptable salt thereof,
g) an acid sulphonamide, preferably Nimesulide or a pharmaceutically acceptable salt thereof.

7 Process as claimed in claim 1, wherein said active substance meloxicam and said physiologically acceptable dispersion medium is an aqueous buffer system with a pH in the range from 2-4.
8 Process as claimed in claim 1 or 7, wherein said physiologically acceptable dispersion medium is a mixture of a physiologically acceptable aqueous buffer system with a pH in the range from 2-4 with other physiologically acceptable liquids, preferably with glycerol and/or optionally aqueous solutions of sugar alcohols such as sorbitol, mannitol and xylitol or mixtures thereof which are suitable for improving specific properties of the suspension.
9 Process as claimed in claim 7 or 8, wherein said physiologically acceptable dispersion medium is a buffer system selected from:

a) sodium dihydrogen phosphate dihydrate/citric acid monohydrate,
b) glycin/HCl,
c) Na-citrate/HCl,
d) K-hydrogen phthalate/HCl,
e) citric acid/phosphate,
f) citrate-phosphate-borate/HCl and
g) Britton-Robinson buffer.
10 Process as claimed in claim 8, wherein said dispersion medium
consists of a mixture of 30-50% aqueous sodium dihydrogen
phosphate dihydrate/citric acid monohydrate buffer, 10-20%
glycerol, 10-20% xylitol and 20-30% sorbitol or mannitol

solution, the sorbitol or mannitol solution being a 70% aqueous
solution.
Process as claimed in claim 1, wherein said suspension
contains as active substance 0.050 to 3.000 g/118 g of
meloxicam, based on the mass of the preparation ready for use,
and optionally one or more flavourings and/or one or more
sweeteners and/or conventional excipients and/or preservatives
which are effective at the pH range.
Process as claimed in claim 1, wherein said active substance is
an acid enolcarboxamide, preferably meloxicam, and
(i) a particle size spectrum is produced in which about 90%
of the particles are smaller than 10 µm, (ii) the ground active substance is suspended in a physiologically acceptable, aqueous buffer system at a pH in the range from 2-4, for example sodium dihydrogen phosphate dihydrate/citric acid monohydrate buffer, glycine/HC1, K-hydrogen phthalate/HCl, citric acid/phosphate, citrate-phosphate-borate/HCl or Britton-Robinson buffer, mixtures thereof with one another or mixtures thereof with other physiologically acceptable liquids such as glycerol or optionally aqueous solutions of sugar alcohols such as sorbitol, mannitol and xylitol, (iii) with the aid of a mixer by the application of high shear forces, characterized for example by a circumferential rotor speed of 15 to 35 m/s, preferably 20 to 30 m/s, 0.1-5.0 wt.-% of highly dispersed silicon dioxide, based on the weight of the suspension ready for use, are added to the dispersion medium, (iv) water soluble cellulose ethers of pharmaceutical grade, preferably hydroxyethylcellulose are added to the dispersion medium as hydrophilic polymers in an amount

of from 0.05 - 2 wt.-%, based on the weight of the suspension ready for use, and (v) one or more flavourings, one or more sweeteners, conventional excipients or one or more preservatives may optionally be added independently of one another to the dispersion medium. Dated this 4th day of August, 2000.
i
[Dr. Ramesh Kumar Mehta]
of Remfry & Sagar
-7-
Attorney for the Applicants

Documents:

abstract1.jpg

in-pct-2000-00266-mum-cancelled pages(07-06-2004).pdf

in-pct-2000-00266-mum-claims(granted)-(07-06-2004).doc

in-pct-2000-00266-mum-claims(granted)-(07-06-2004).pdf

in-pct-2000-00266-mum-correspondence(17-06-2004).pdf

IN-PCT-2000-00266-MUM-CORRESPONDENCE(26-3-2010).pdf

in-pct-2000-00266-mum-correspondence(ipo)-(16-12-2002).pdf

IN-PCT-2000-00266-MUM-CORRESPONDENCE(IPO)-(19-6-2009).pdf

in-pct-2000-00266-mum-drawing(07-06-2004).pdf

in-pct-2000-00266-mum-form 1(07-06-2004).pdf

in-pct-2000-00266-mum-form 13(05-05-2003).pdf

in-pct-2000-00266-mum-form 2(granted)-(07-06-2004).doc

in-pct-2000-00266-mum-form 2(granted)-(07-06-2004).pdf

IN-PCT-2000-00266-MUM-FORM 26(26-3-2010).pdf

in-pct-2000-00266-mum-form 3(04-08-2000).pdf

in-pct-2000-00266-mum-form 4(25-02-2004).pdf

in-pct-2000-00266-mum-form 5(04-08-2000).pdf

in-pct-2000-00266-mum-petition under rule 137(07-06-2004).pdf

in-pct-2000-00266-mum-petition under rule 138(07-06-2004).pdf

in-pct-2000-00266-mum-power of authority(07-06-2004).pdf

in-pct-2000-00266-mum-power of authority(11-07-2000).pdf

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Patent Number

205268

Indian Patent Application Number

IN/PCT/2000/00266/MUM

PG Journal Number

25/2007

Publication Date

22-Jun-2007

Grant Date

23-Mar-2007

Date of Filing

04-Aug-2000

Name of Patentee

BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG.

Applicant Address

BINGER STRASSE 173, D-55216 INGELHEIM AM RHEIN, GERMANY.

Inventors:

#	Inventor's Name	Inventor's Address
1	DIETRICH TURCK	KONIGSTRASSE 55, 89077 ULM, GERMANY
2	VEIT SCHMELMER	HUHNERFELDSTRASSE 24, 88400 BIBERACH, GERMANY

PCT International Classification Number

A61K 9/00,47/02

PCT International Application Number

PCT/EP99/01948

PCT International Filing date

1999-03-23

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA